Enhanced sampling by multiple molecular dynamics trajectories: Carbonmonoxy myoglobin 10 μs A₀ → A_1-3 transition from ten 400 picosecond simulations

The utility of multiple trajectories to extend the time scale of molecular dynamics simulations is reported for the spectroscopic A-states of carbonmonoxy myoglobin (MbCO). Experimentally, the A₀→A_1-3 transition has been observed to be 10μs at 300K, which is beyond the time scale of standard molecular dynamics simulations. To simulate this transition, 10 short (400ps) and two longer time (1.2ns) molecular dynamics trajectories, starting from five different crystallographic and solution phase structures with random initial velocities centered in a 37Å radius sphere of water, have been used to sample the native-fold of MbCO. Analysis of the ensemble of structures gathered over the cumulative 5.6ns reveals two biomolecular motions involving the side chains of His64 and Arg45 to explain the spectroscopic states of MbCO. The 10μs A₀→A_1-3 transition involves the motion of His64, where distance between His64 and CO is found to vary up to 8.8±1.0Å during the transition of His64 from the ligand (A _1-3) to bulk solvent (A₀). The His64 motion occurs within a single trajectory only once, however the multiple trajectories populate the spectroscopic A-states fully. Consequently, multiple independent molecular dynamics simulations have been found to extend biomolecular motion from 5ns of total simulation to experimental phenomena on the microsecond time scale.